Effect of intrathecal ACEA-1021 in a rat model for postoperative pain

Drugs antagonizing glycine at the N-methyl-D-aspartate (NMDA) receptor have been developed to improve efficacy, increase specificity, and, perhaps, re duce side effects. The purpose of this study was to examine the effect of i ntrathecally (IT) administered ACEA-1021, a glycine receptor antagonist at the NMDA receptor complex, in a rat model of postoperative pain. Rats with IT catheters were anesthetized and underwent a plantar incision. Two hours later, withdrawal threshold to punctate stimulation was determined by apply ing calibrated von Prey filaments adjacent to the wound. In another group, the response frequency to a plastic disk, a blunt, nonpunctate mechanical s timulus applied directly on the incision also was measured. In unincised ra ts, NMDA, alpha -amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA), or kainate (KA) was administered IT 30 minutes after ACEA-1021 or vehicle. Spontaneous nociceptive behaviors (SNB) caused by IT excitatory amino acid s (EAAs) were counted. In the vehicle-treated group, the median withdrawal threshold for punctate stimulation decreased from 522 mN before incision to 61 mN or less for 4 hours after incision. In 3 separate groups, the median withdrawal threshold increased to 61, 118, and 332 mN 30 minutes after IT administration of 10, 30, and 60 nmol of ACEA-1021, respectively. In 3 othe r groups, IT administration of 10, 30, and 60 nmol of ACEA-1021 decreased t he response frequency to the blunt mechanical stimulus from 95 +/- 13 or gr eater to 78 +/- 40%, 67 +/- 37%, and 22 +/- 27% 30 minutes after drug injec tion, respectively. Sixty nmol of ACEA-1021 inhibited SNBs caused by IT NMD A, KA, and AMPA. IT administration of ACEA-1021 decreased incision-induced pain behaviors in this rat model. ACEA-1021 blocked SNB by NMDA, KA, and AM PA. These data, coupled with previous studies, suggest that inhibition of p ain behaviors by IT ACEA-1021 is produced by blockade of spinal non-NMDA re ceptors.